Sodium-Dependent Neutral Amino Acid Transporter 2 Can Serve as a Tertiary Carrier for l‑Type Amino Acid Transporter 1‑Utilizing Prodrugs

Membrane transporters
are the key determinants of the homeostasis
of endogenous compounds in the cells and their exposure to drugs.
However, the substrate specificities of distinct transporters can
overlap. In the present study, the interactions of l-type
amino acid transporter 1 (LAT1)-utilizing prodrugs with sodium-coupled
neutral amino acid transporter 2 (SNAT2) were explored. The results
showed that the cellular uptake of LAT1-utilizing prodrugs into a
human breast cancer cell line, MCF-7 cells, was mediated via SNATs
as the uptake was increased at higher pH (8.5), decreased in the absence
of sodium, and inhibited in the presence of unselective SNAT-inhibitor,
(α-(methylamino)isobutyric acid, MeAIB). Moreover, docking the
compounds to a SNAT2 homology model (inward-open conformation) and
further molecular dynamics simulations and the subsequent trajectory
and principal component analyses confirmed the chemical features supporting
the interactions of the studied compounds with SNAT2, which was found
to be the main SNAT expressed in MCF-7 cells.